<i>MIR137</i> polygenic risk is associated with schizophrenia and affects functional connectivity of the dorsolateral prefrontal cortex

Liu, Shu; Li, Ang; Liu, Yong; Li, Jin; Wang, Meng; Sun, Yuqing; Qin, Wen; Yu, Chunshui; Jiang, Tianzi; Liu, Bing

doi:10.1017/s0033291719001442

Cited by 12 publications

(4 citation statements)

References 58 publications

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“…PRS based on biologically driven gene-sets may outperform the genome-wide PRS in explaining brain phenotypes. Examples of that are recent studies attempting to identify 'core gene-sets' that make a larger contribution to SZ risk 17 , or to predict brain anatomy 18 and functional connectivity 19 via PRS limited to genes up-or down-regulated by MIR137 20 .…”

Section: Introductionmentioning

confidence: 99%

Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort

et al. 2020

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Research has shown differences in subcortical brain volumes between participants with schizophrenia and healthy controls. However, none of these differences have been found to associate with schizophrenia polygenic risk. Here, in a large sample (n = 14,701) of unaffected participants from the UK Biobank, we test whether schizophrenia polygenic risk scores (PRS) limited to specific gene-sets predict subcortical brain volumes. We compare associations with schizophrenia PRS at the whole genome level (‘genomic’, including all SNPs associated with the disorder at a p-value threshold < 0.05) with ‘genic’ PRS (based on SNPs in the vicinity of known genes), ‘intergenic’ PRS (based on the remaining SNPs), and genic PRS limited to SNPs within 7 gene-sets previously found to be enriched for genetic association with schizophrenia (‘abnormal behaviour,’ ‘abnormal long-term potentiation,’ ‘abnormal nervous system electrophysiology,’ ‘FMRP targets,’ ‘5HT2C channels,’ ‘CaV2 channels’ and ‘loss-of-function intolerant genes’). We observe a negative association between the ‘abnormal behaviour’ gene-set PRS and volume of the right thalamus that survived correction for multiple testing (ß = −0.031, pFDR = 0.005) and was robust to different schizophrenia PRS p-value thresholds. In contrast, the only association with genomic PRS surviving correction for multiple testing was for right pallidum, which was observed using a schizophrenia PRS p-value threshold < 0.01 (ß = −0.032, p = 0.0003, pFDR = 0.02), but not when using other PRS P-value thresholds. We conclude that schizophrenia PRS limited to functional gene sets may provide a better means of capturing differences in subcortical brain volume than whole genome PRS approaches.

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Section: Introductionmentioning

confidence: 99%

Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort

et al. 2020

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“…Bioinformatics analyses predicted the presence of a miR-137 seed region in the MSH2 3′UTR—with our in vitro results confirming MSH2 is targeted by miR-137. MiR-137, which is located on human chromosome 1p22, is reportedly present in neuronal cells [ 37 , 38 , 39 , 40 ], but is also found constitutively expressed in normal colonic epithelium [ 27 , 28 , 41 , 42 , 43 , 44 ], while low expression is found in adenomatous polyps and tumoral colorectal tissues [ 21 ]. Moreover, miR-137 locus is frequently hypermethylated in several tumor types, including colorectal, gastric, breast, head and neck squamous cell carcinoma, and colorectal adenomatous tissue [ 45 , 46 , 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

MiR-137 Targets the 3′ Untranslated Region of MSH2: Potential Implications in Lynch Syndrome-Related Colorectal Cancer

Liccardo

Sessa

Trombetti

et al. 2021

Cancers

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Mismatch Repair (MMR) gene dysregulation plays a fundamental role in Lynch Syndrome (LS) pathogenesis, a form of hereditary colorectal cancer. Loss or overexpression of key MMR genes leads to genome instability and tumorigenesis; however, the mechanisms controlling MMR gene expression are unknown. One such gene, MSH2, exerts an important role, not only in MMR, but also in cell proliferation, apoptosis, and cell cycle control. In this study, we explored the functions and underlying molecular mechanisms of increased MSH2 expression related to a c.*226A>G variant in the 3′untranslated (UTR) region of MSH2 that had been previously identified in a subject clinically suspected of LS. Bioinformatics identified a putative binding site for miR-137 in this region. To verify miRNA targeting specificity, we performed luciferase gene reporter assays using a MSH2 3′UTR psiCHECK-2 vector in human SW480 cells over-expressing miR-137, which showed a drastic reduction in luciferase activity (p > 0.0001). This effect was abolished by site-directed mutagenesis of the putative miR-137 seed site. Moreover, in these cells we observed that miR-137 levels were inversely correlated with MSH2 expression levels. These results were confirmed by results in normal and tumoral tissues from the patient carrying the 3′UTR c.*226A>G variant in MSH2. Finally, miR-137 overexpression in SW480 cells significantly suppressed cell proliferation in a time- and dose-dependent manner (p < 0.0001), supporting a role for MSH2 in apoptosis and cell proliferation processes. Our findings suggest miR-137 helps control MSH2 expression via its 3′UTR and that dysregulation of this mechanism appears to promote tumorigenesis in colon cells.

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“…All the subjects were told to stay awake, close their eyes, and avoid movement during the scanning. More detailed data acquisition and preprocessing details can be found in our previous study (Liu et al, 2020).…”

Section: Processing Of Normal Resting-state Functional Mr Imaging (Rs...mentioning

confidence: 99%

Unruptured brain arteriovenous malformations causing seizures localize to one common brain network

Zhao

Liao

et al. 2022

J of Neuroscience Research

Self Cite

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Seizures are a frequent symptom of unruptured brain arteriovenous malformations (bAVMs). However, the brain regions responsible for these seizures remain unclear. To identify the brain regions causally involved in bAVM-related seizures, we retrospectively reviewed 220 patients with unruptured bAVMs. Using voxel-based lesion-symptom mapping (VLSM) analyses, we tested whether individual brain regions were associated with unruptured bAVM-related seizures. The result revealed that unruptured bAVMs causing seizures are anatomically heterogeneous at the voxel level. Subsequently, lesion network mapping (LNM) analyses was performed to determine whether bAVMs causing seizures belonged to a distributed brain network. LNM analyses indicated that these lesions were located in a functional network characterized by connectivity to the left caudate and precuneus. Moreover, the discrimination performance of the identified seizure network was evaluated in discovery set by calculating the individualized network damage score and was tested in validation set. Based on the calculated network damage scores, patients were divided into low-, medium-, and high-risk groups. The prevalence of seizures significantly differed among the three risk categories in both discovery (p = .003) and validation set (p = .004). Finally, we calculated the percentage of voxels in the canonical resting-state networks that overlapped with the seizure-susceptible brain regions to investigate the involvement of resting-state networks. With an involvement percentage over 50%, the frontoparietal control (82.9%), limbic function (76.7%), and default mode network (69.3%) were considered to be impacted in bAVM-related seizures. Our study identified the seizure-susceptible brain regions for unruptured bAVMs, which could be a plausible neuroimaging biomarker in predicting possible seizures.

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MIR137 polygenic risk is associated with schizophrenia and affects functional connectivity of the dorsolateral prefrontal cortex

Cited by 12 publications

References 58 publications

Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort

Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort

MiR-137 Targets the 3′ Untranslated Region of MSH2: Potential Implications in Lynch Syndrome-Related Colorectal Cancer

Unruptured brain arteriovenous malformations causing seizures localize to one common brain network

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